Full Year 2020 Taysha Gene Therapies Inc Earnings Call
Welcome to the tastes of gene therapies full year 2020 financial results and corporate update conference call. At this time all participants are in a listen only mode. Following the management's prepared remarks, we will hold a brief question answer session at the.
The reminder of this call is being recorded today March 3rd 2021, I will now turn the call over to Dr. Kimberly Lee Senior Vice President of corporate Communications and Investor Relations. Please go ahead.
Yeah.
Thank you and good morning, and welcome Cretaceous full year 2020 financial results and corporate update conference call. Joining me on today's call are are a session of the second cash as president CEO and founder Dr. C. S Prasad Chief Medical Officer and head of IR.
Randy and Kamran Alam Chief Financial Officer.
After our formal remarks, we will conduct a question and answer session and instructions will follow at that time.
Earlier today tissue of issued a press release announcing financial results for the full year ended December 31st 2020.
A copy of the press release is available on the company's website and through our SEC filings.
Please note that on today's call, we will be making forward looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational drug candidate <unk>.
These statements May include the expected timing and results of clinical trials for our drug candidates and the regulatory status and market opportunity for those programs as well as patients manufacturing plants.
This call May also contain forward looking statements relating to <unk> growth and future operating results the discovery and development of drug candidates.
Jake alliances in the intellectual property, that's why it matters that are not historical facts or information various risks may cause patients actual results could differ materially from those stated or implied in such forward. Looking statements. These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of our drug.
Our dependence upon strategic alliances and other third party relationships.
The ability to obtain patent protection for our discoveries limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities.
Boiler and description of the risks and uncertainties that we face. Please see the reports we have filed with the Securities and Exchange Commission.
This conference call contains time sensitive information that is accurate only as of the date of this live broadcast March 3rd 2021 patient undertakes no obligation to revise or update any forward looking statements to reflect events or circumstances. After the date of this conference call, except as may be required by applicable securities.
La I would now like to turn the call over to our president CEO and founder or a session. The second.
Thank you Ken Good morning, and welcome everyone to our gross corporate update and financial results Conference call. We.
We hope you and your family continue to remain safe and healthy.
In the past year, we have made significant progress in our corporate initiatives.
Elaborate on some of our key achievements and upcoming expected milestones and then we'll turn the call over to Sue you shouldn't Cameron for updates on that.
Pipeline developments and financial results respectively.
2020 finally the.
Successful and foundational year for the company marked by many significant milestones.
Since March 2020, we have raised gross proceeds.
$307 million, which included approximately $181 million in gross proceeds from the completion of the successful IPO lack of timber that included participation from a significant number of high quality health care focused institutional investors, which increased our visibility within the broader investing.
The community.
This was one of the fastest seed to Ipos in biotech history, which we consider a reflection of the team's commitment and our investors' confidence and our innovative approach to gene therapy.
Central to <unk> success is our strategic collaboration with the UT Southwestern Medical Center Gene therapy program.
One of the Premier academic medical centers in the World.
We hold an exclusive worldwide royalty free license from Ut southwestern to discover develop and commercialize gene therapies for our pipeline.
Our collaboration with UT southwestern is led by Dr. Steven Great embarrassment of assay Dr.
Dr. Greg is the associate professor in the department of Pediatrics at Ut southwestern and an expert in the development of AAV based gene therapies for the CNS disorders Dr.
Dr. <unk> been asking is the division chiefs of child, Neurology and faculty.
The children's Medical Center of Research Institute at UT southwestern and he sees in the clinician and the diagnosis management and treatment of rare pediatric neurological diseases.
Through our partnership we are advancing a deep and sustainable pipeline. The currently consists of 25 gene therapy product candidate our portfolio targets monogenic diseases of the central nervous system across three distinct franchises neuro degenerative diseases, neurodevelopmental disorders and genetic epilepsy.
By leveraging synergies across our programs, we are well positioned to advance our current pipeline why while actively developing our novel next generation platforms to expand the limits of gene therapy into indications that are currently under addressable with the available technologies.
We are complementing our efforts to expedite the development of our current programs by working closely with regulatory authorities and we have already secured rare pediatric disease, an orphan drug designations from the FDA.
Sixth product candidates pace of 101, Virginia, <unk> Gangliosidosis peso of one or two per ret syndrome patient one three for the six.
Six day, one affluent insufficiency.
One of 4% one associated leased and Duane pace of mental Fi the SLC <unk> deficiency and pace of 118 or ceiling, one infantile batten disease.
Our relationship with patient advocacy organizations and research foundations remain very important to us.
As such we continue to establish further strategic partnerships, including with <unk> and all strength to support access to genetic testing and earlier diagnosis of patients with CNS disease.
And to inform the understanding of the natural history disease burden and patient diagnostic journey. We believe this will also accelerate our efforts to enroll patients for clinical trials.
Part of our approach to accelerate the development of our pipeline is integrating our R&D and GMP manufacturing capabilities.
To sufficiently meet the clinical demand of our extensive portfolio.
Our three pillar approach to manufacturing includes our partnership with Ut southwestern where we have access to a 500 liter GMP compliant manufacturing suite, the early phase clinical and R&D, enabling toxicology materials.
And our manufacturing partnership with Cadillac the early phase and pivotal clinical supply the <unk>.
Third pillar is the establishment of our internal of 187000 square foot commercial scale GMP compliant manufacturing facility with multiple production suites and in the initial capacity of 2000 leaders to support preclinical through commercial GMP manufacturing for our pipeline.
We believe the addition of an internal facility will enable us to drive efficiencies and scalability across our manufacturing supply chain in order to meet the potential demand of our multiple concurrent programs. We expect to initiate construction on this facility later this year.
As part of our manufacturing strategy. We are also spending time and effort on CMC characterization potency assay tighter in the assays and other associated lab work.
Our employees are foundational to our ability to quickly advance the development of gene therapies.
Asia is growing at such an incredible pace that we have more than doubled our employee base to approximately 80 and just the last three months. Moreover, we expect to expand the team to approximately 150 employees by year end to support our robust development and corporate initiatives.
We are privileged to have our efforts augmented through partners and advisers, who are trailblazers in the gene therapy space. The R&R strategic collaboration with Dr. Gray and the nasty here we are.
We're fortunate to be advised by the independent internationally renowned scientific advisory board with academic credibility and significant industry experience and the seasoned board of directors, consisting primarily of the industry, leading gene therapy executives intact.
With their support we believe we are uniquely positioned for sustained success as we further our R&D initiatives and advance our next generation technology platforms.
We anticipate a transformational year as we expect to report first in human clinical data for Taishan, one of them one in <unk> Gangliosidosis and launch four candidates into phase one slash two studies following acceptance of their IND or Cta as well.
We are currently advancing an additional five therapies into I N D or Cta, enabling studies and have initiated four new programs into preclinical development.
Importantly, we expect to advance our next generation technologies to optimize key components of AAV based gene therapy, we look forward to leverage our capabilities to pioneer novel approaches to address vector capacity and to continue to innovate as it pertains to payload design.
Lastly, we will continue to evaluate opportunities to maximize the value of our existing pipeline.
I will now turn the call over to <unk> to provide an update on our R&D initiatives fish. Please go ahead.
Thanks, Alright.
As already mentioned <unk> has a robust portfolio of 25 gene therapy product candidates from monogenic diseases of the CNS all.
All candidates targeting broad therapeutic categories of immense unmet medical need, including neuro degenerative diseases neurodevelopmental disorders of genetic epilepsies.
Our approach to developing gene therapies census from the use of AAV nine delivered directly to the street respond the fluid or CSF using interest equal administration.
We believe the interest equally delivered 89 based gene therapies are the price Kristen valley's methods of delivering gene therapy to treat neurological disease.
Each has some clinical precedent now.
AEP non has been widely characterized across numerous preclinical and completed clinical trials and has a well delineated by the distribution.
Safety Tolerability and efficacy profile.
In comparison to other AAV serotypes AAV non administration through lumbar interest equal injection has been shown to result in significant transduction of multiple source within the CNS and the clinical benefit and some therapy areas.
We manufacture our product candidates using mammalian at Tucson of three suspension based process designed to efficiently scale sports of clinical and commercial development needs.
The utilization of the AAV non cash it across our product portfolio enables us to manufacture each part of the with minimal process changes to salt product comes as one of the Thailand, specifically the therapeutic transgene.
We believe this combination of aging on manufacturing to suspension until of interests equally will allow us to effectively and efficiently advance the gene therapy candidates in our product pipeline.
One of our lead near the Genesis disease product candidates is patient one of the one which is currently in the phase one two trial for the treatment of the infantile gene to Kansas The doses, which include the Ty-sachs disease on Sandoz disease.
GMT cognizant of those business unless of several stores just all of the resulting from a deficiency in the beats the heck sense of midsize I emphasize often referred to as heck site, leading to an accumulation of <unk> ganglioside lysosomes, the rental cell damage and ultimately neuronal cell death.
There are no approved therapies for the treatment of GM to Congress of doses on cash is generally palliative.
The most covenants the vessel is infantile G&P countless of doses, which approximately 80% to 85% of patients diagnosed with this fall.
<unk> kind of Pseudocyst is characterized by X sight, and some activity levels less of 1% while <unk> gangliosidosis is characterized by hexane enzyme activity, let's just 5% to 2% of normal activity.
Children, usually present in the symptoms in the first few weeks of life and the experience.
Neuro degeneration, culminating in depth for the age of full.
Patients with juvenile Chimps U can English of doses rarely survive beyond the mid teens.
I felt onset gene to Kansas the doses patients have heck site enzyme activity levels typically in the range of 2% to 4% of normal hex activity and mainly the normal lifespan.
<unk>, having some considerable cognitive on euro of psychiatric challenges.
We believe that reached the level of 5% of normal hikes of activity will result in the significant reduction in the cumulative substrates and the improvements in clinical outcomes.
It is important of the exercise of the Hetro toddler, consisting of an alpha subunit of the beta subunits.
What's unique about Taishan one of the one that is that this is the first and only buys the straw that trans gene in clinical development.
By linking of the human Heck site speed genes, which of the gene that codes of the alpha subunit of the beta subunits of beta access of minutes.
Haven't been being driven off the same promotion, we are ensuring the expression of each subunits of the tax estimates.
At the appropriate one to one ratio within each cell.
We believe this is the most efficient way to produce high levels of functioning heterodyne Merrick per site within each cell.
In preclinical studies, we observed significant improvement in survival in mice across all dose levels of interest equally administered takes you 101 as compared to mice treated with the vehicle alone.
We observed the symbol of dose dependent response in behavioral assessments of mice evaluation, but it is a function of the dose dependent decrease in ganglioside, the accumulation of brain tissue.
All of which suggest a restoration of <unk> enzyme activity.
Notably no adverse findings or evidence of toxicity attributable to <unk> of 101.
The net.
In December Queen's University, Ontario received approval of its clinical trial application or Cta from health, Canada for US phase one two clinical trial of tissue of 101 in patients with infantile GM to kind of goes through that assists.
Patients will be evaluated from one yet within the additional longer term extension parents to monitor ongoing safety developmental progression and select efficacy measures.
In addition to evaluating safety and Tolerability. The key efficacy endpoints will include Biomarkers, the assessments of Hypotonia and motor function.
As noted earlier, we believe this achievement five per cent hexane enzyme activity in CSF will result in the considerably improved clinical phenotype, we would consider that a positive outcome.
Queen's University expects to report preliminary safety and biomarker data in the second half of 2021.
And the U S. We intend to submit the 90 in the second half of 2021 of if accepted we intend to initiate the phase one two trial in the second half of this year.
We're also working to address the progressive fatal neuro degenerative disease CLO one.
So you like the one disease is a rare lysosomal storage disorder caused by loss of function mutations in the scale of one gene which results in the lack of the enzyme <unk> protein of fine Westernized, Paul PBT of one.
Our product candidate patient of one eight is designed to achieve a functional CLR one gene using an AAV non factor and that has the potential to be the first disease modifying therapeutic for this disease.
Preclinical studies, demonstrating the interest equal treatment with takes you wouldn't one eight significantly extended survival of CLR, one knockout mice with enhanced survival of behavioral outcomes correlating with treat in the type of younger ages.
We expect to initiate the phase one two clinical trial of tissue overnight and the <unk>.
Second half of this year under our currently open int.
The trial is expected to enroll up to 18 patients with sale of one disease with primary endpoints evaluating safety and the Frankfurt developmental milestones.
After the lead come to that price you wanted to say is in development for the treatment of ret syndrome of severe neurodevelopmental disorder.
In most cases caused by the loss of function mutations in the <unk> two gene.
And the C. P. Two of <unk> pizza is of protein essential from neuro little on synaptic function and the bright.
For effective treatment mcafee to expression of needs to be titrated to correct. The <unk> deficiency, whilst avoiding the adverse effects associated with too much Mec pizza.
Given the Ret syndrome is an X linked dominant disease and thus the patients saw mosaics with differential expression of <unk> two of different styles. The regulation of the PT to appropriate levels needs to occur on the <unk>.
I'll buy sell basis.
Accordingly to prevent harmful those sorts of trends gene expressing factors, while affording subsidiary of pizza and levels of Thomas the ETS W. Have designed it proprietary methods of trends gene regulation cold.
Right.
Cool micro RNA also regulatory elements.
Am I right as a novel MLR of nice target channel positioned in the untranslated region of the genotype of the construct that.
Following the adoption of this down regulatory micro Rnas, that's all activated in the presence of high levels of net pizza.
Through this approach take care of one or two is designed to maintain transgene expression levels in the south of the price within the appropriate physiological parameters.
In preclinical studies tasteful one of the two demonstrated the favorable tolerability profile in wild type mice and increased survival in the knockout mouse model.
We intend to submit the 90 or Cta if it takes you wanted to in the second half of this year and to initiate a phase <unk> trial by the end of the year, which will evaluate safety tolerability and preliminary efficacy.
We are proud to say the we have transitioned from a preclinical to a clinical stage company and we continued to build momentum on our R&D initiatives.
This year, we plan to initiate four phase <unk> trials and advanced full product candidates into IND or Cta, enabling studies as well as full new undisclosed programs into preclinical studies.
We will continue to work closely with the FDA on the other regulatory agencies to advance of Kansas through development to potential commercialization.
Importantly, we will continue to advance of sustainable pipeline by leveraging our next generation platform technologies.
Part of this initiative, we recently established the collaboration with Dr. Dennis Law of the Genomics Institute. Please wound clinic to further push the boundaries of AAV vector engineering by developing next generation. Many gene payload that has the potential to overcome current limitations of packaging capacity, which is of critical barrier to treat.
Genetic diseases lots of addressable by conventional AAV gene therapy technologies.
This may enable us to effectively treat a wider range of devastating CNS diseases.
Also continues to develop new construction at the end of the actual new payloads in partnership with Ut southwestern.
With that I'll turn the call over to Cameron to review of financial results.
Thank you <unk> this.
This morning, I will discuss key aspects of our full year 2020 financial results more details can be found in our form 10-K, which will be filed with the SEC shortly.
As indicated in our press release today R&D expenses were $31 $9 million per the year ended December 31, 2020 compared to $1 million from company inception on September 20th 2019 to December 31 2019 the.
Encouraged was primarily due to the Companys development programs as a result of increased manufacturing related spending clinical and preclinical activities and head count.
G&A expenses were $11 $1 million for the year ended December 31, 2020, compared to zero point $1 million from company inception on September 20 of 2019 to December 31 2019 the.
The increase was primarily due to an increase in personnel costs, resulting from increased headcount professional service fees and other corporate related expenses.
Other expenses were $17 million for the year ended December 31, 2020, which were noncash in nature and represented the change in fair value of the preferred stock tranche liability associated with the series a convertible preferred stock.
Net loss for the year ended December 31, 2020 was $60 million or $3 40 per share as compared to a net loss of $1 $1 million or <unk> 12 cents per share for the period from company inception on September 20th of 2019 to December 31 2019.
We ended 2020 with $251 $3 million from cash and cash equivalents, which included the $165 $9 million in net proceeds from the company's IPO completed in September 2020.
We expect that our working capital will be sufficient to fund operations into 2023, which includes the development regulatory and operational milestones are a outlined earlier and with that I'll hand, the call back to Ara.
Thanks Cameron.
As you heard we had an extremely productive 2020 and are excited and energized to execute on our operational goals for 2021.
We believe our robust pipeline reflects the power and potential of the platform by leveraging our unique strength and the many synergies across all programs, we would expect to drive future sustained innovation of that tightening.
From a strategic standpoint collaborations have been the cornerstone of pace of success to date, and we will continue to evaluate other opportunities to maximize the value of our existing portfolio as well as the potentially expanded.
Persistence and dedication, we will continue to strive towards creating and capturing value as we advance our gene therapy programs into the clinic and expand our product pipeline of novel CNS treatment options in the months and years ahead.
I will now ask the operator to begin our Q&A session operator.
Thank you how does the reminder to ask the question you'll need the press star one on your telephone to withdraw your question in terms of the balance sheet day stay involved with some part of the Q&A roster.
Our first question comes from <unk> Richter with Goldman Sachs. You May proceed with your question.
Good morning, and thank you from taking a question with as well as the both on the profile of <unk> could you remind us of what would be clinically meaningful and sort of what you're looking for in the clinical data.
Two at year end 'twenty, one specifically as it relates to Hypotonia and the motor function improvement you mentioned and then similarly on your initial thoughts on what you would be hoping to see from the first data and surf one thank you.
We appreciate the question so what I'll do is I'll turn it over the two years and three years could address this question. So yes.
Thanks, Alright, thanks Elizabeth.
Yes G M too so as gene.
We have an outcome on the equivalent of Ctrip and <unk>.
The.
The guidance of biomarker data during the second half of this year and clinical data.
<unk> preliminary clinical data by the end of this year. So in terms of what we're expecting to see and what we believe would be clinically meaningful I think the first thing we will see is an increase in the biomarker activity, specifically hex PE in the CSF since the enzyme the <unk>.
The missing and GM to languish at doses of the tax estimates eyesight and I expect what will happen is it will dose of patient interest the equally.
We will.
Take CSF samples of subsequent to that the first simple will be one month after dosing and I would expect to see an increase in volume on productivity.
At the time point now as you might recollect.
The different phenotypes of GM to different levels of underlying biomarker activity. The infantile form which is most of the progressive runs at.
Less than 1% activity the juvenile forms.
Which.
Serious disease, but usually results from that from the teams from between.
About <unk>, 5%, Tennessee, and the adequate answer form of the normal life expectancy, usually around between two and four percents activity. So we actually think of that.
Lifting of the biomarker level up to about 5% will result in I.
Really dramatically improved clinical phenotype, so I would hate to say that we would consider that.
Significant improvement from the bond market perspective.
Which of them. So I think we will see relatively early on we will see some improvement by about the one month time points and all types of see further proof of about three months of time points of which point, we will take until the CSF sample.
Of that biomarker activity from.
The clinical efficacy perspective.
The kinds of endpoints. We're looking at of course, we were looking at safety and Tolerability of this phase one two study.
And then.
Gross Molson find most of the milestones specifically things such as the ability of self price.
The ability to reach out grasping objects.
The ability to fix the following.
And the specific milestone as it will be a little bit dependent on the age of the child, but we should see a stabilization or a low.
Lack of ongoing regression of milestones of certainly the preliminary clinical data.
In addition to that we'll be looking at scale. So from the chop intend the bayley scale.
Volume loans adaptive behavior of scale.
And all of these assessments will be videos uploaded to the silver and then the.
The kind of double school of upon the external racer.
Moving to the seizure activity frequency of medications.
Quality of life in the Catholic the burden of assessments now the <unk>.
The improvement will say, it's a little unclear of what I think we should see so the stabilization or an ongoing halting of progression and this will be somewhat dependent on how the victory. The treat the children. The intent is to treat the children.
The as possible before the ongoing progressive and you're one of the loss of some chance to take hold.
And therefore allow for that.
As much recoverability and reverse the ability of the disease as possible.
Let me stop of the hedge loss can be some context of what we expect to see over the next the coming yet.
And so you said I believe there was the question on on surf one and maybe we just want to comment on Cox activity citrate levels in lactate.
Of course, yes, sorry.
It was the second part of the question of course, just said if one of the much control of disease and.
Once again I would think of the endpoints from two groupings the.
The market type of endpoints and also clinical specifically specific endpoints, so clinical amongst the progression.
On the biomarker side of things the marks were looking at Cox activity.
Which is the.
Aspects of the popular spirit free chain.
The fact of in much control of disease.
We'll also be looking at lactate levels of par rate levels now from the lack of taste and par rate perspective with some of these much control diseases.
And to remind yourself one is the commonest cause of such kind of sales base deficient leak syndrome, which which presents huge in the first year of locked with the severe neurological disorder.
Yes.
And.
From a biomarker perspective, we'll be looking at.
The cost of activities on site, but also of lactate levels, which are an indicator of the fact that the.
He is.
The producing energy on the rope of fleet, rather quickly because of the much country of dysfunctional and the situations. So the lactate levels of UC elevate to the baseline both in the serum.
In the CSF and has.
I'm on the exercise, you'll actually see a much greater increase in lactate levels in the world and the normal healthy.
Mitchell so what we should see his treatment.
Takes hold as the nice.
The improvement in Cox activity side of this is an improvement in the actual respiratory function.
A function of the the restricted chain the production of on the sheet, but also a drop in lactate levels and one of them. The stop loss of market power of eight vessels of the biomarker side on the clinical side will be performing many of these developmental milestones once again some of the bayley scale the GM FM the chalk.
Specifically, the so much come drill disease skills will be looking at such as the new castle of pediatric much controversy scale of the NP.
Pds.
And then of course, the cheese mris.
She function because of the respiratory function, specifically breathing function as opposed to restrict the chain function is also significantly compromising children with cellphone deficiency.
With the right things of that answer your question, yes. It does thank you. Thank you.
Thank you. Our next question comes from both of them simply shutdown. You May proceed with your question.
Hi, Good morning, Thanks for taking my call and congrats on the progress with head count and our product candidate expansion just wanted to touch on the two and maybe tie them together, a little bit but could you discuss your priorities on hiring to get to the 150 on head count expansion by year end and how do you maintain.
The synergies among.
The 25 product candidates in terms of investigating them.
Yeah I appreciate the question Bowl of good morning. So.
I think when you think about head count.
And the way they were going to be hiring this year I think you would see us default heavily towards the R&D side, but obviously, we're gonna be hiring the across the board of across both R&D and corporate function, but I would say the majority of the hiring of it's going to take place primarily in our manufacturing group, obviously, we announced star.
Many of the lease of our 187000 square foot facility, which we've initiated construction on this year and in Durham, and we previously disclosed that upon commissioning that facility will house about 200 employees.
And so the obviously, there's going to be a.
A big push the higher to support that facility in that growth, but will also be hiring of across the board in Cbs's group Ah clinical development clinical operations to support the number of clinical trials that we have ongoing this year and that we anticipate initiating next year as.
As well as in our regulatory group obviously.
The number of submissions across the board both with the FDA and ex U S are going to be substantial and so we're going to need to hire to support that but in general we will need to also increase just general corporate support across the entire organization that means the HR function finance function legal functions, which we've already hired the leadership.
The key positions that it'll be in those guys will be building off of the team. So so that's the way that that we're looking at prioritizing hiring, but but we're heavily defaulting towards the R&D side, the support kind of the the progression of the portfolio, it's moving fast and we wanted to make sure.
That we have the bodies on hand in the resource of on hand to keep it moving.
Greg could you repeat the could you repeat your second question.
It was about synergies, but I think I got a sense of it but.
Could I just shift a little bit of announced how you acquired the last seven product candidates, taking it to 25 I mean for example, why didn't you already have done an IPO and does this mean that there are more opportunities to pull in from Ut southwestern.
Yes, it's a great question. So I think the short answer to your question is yes, they are more opportunities to pull in from Ut southwestern.
The way the we've evaluated opportunities over the last year, it's been quite organic and it's been quite collaborative with our team at Ut southwestern so typically either the taste of the team will come up with it with a target of identify a target that we will like to pursue and then we'll present that at the GSC to Ut southwestern to see if it's feasible.
Fits our strategy and the available technology that we have in our hands today as appropriate.
And so we've been fortunate to be able to identify a number of targets that fit within our three the thing franchises neurodegenerative diseases, neurodevelopmental disorders, and genetic epilepsy and what we've tried to do is in areas, where we think gene therapy can play a role, but may not necessarily be addressable by <unk>.
<unk> technology, we've gone out and sought out partnerships and collaborations to kind of address those limitations similarly to what we've done with the.
Then the flower at Cleveland clinic around genetic epilepsy, and so when you start to think about that that's the considerably opens up the space of what we're able to go after you know there's more than 7000 monogenic.
Diseases to tackle, albeit our focus is going to be on the CNS, but I don't think there's any shortage of of targets to go after where there is a considerable unmet medical need.
Great. Thanks, sorry.
Awesome.
Thank you. Our next question comes from Raju Prasad with William Blair. You May proceed with your question.
Thanks for taking the question and congrats on the progress.
Just a question on on the payload.
Enhancements that you guys are making or the focus on it can you just talk a little bit about.
I know, you're using kind of a single strength.
The <unk>.
Construct for the <unk> program, and then that might of rare program.
Can you just talk a little bit about what you're hoping to learn about those kind of cost structure improvements from these first programs and then I got a question of manufacturing for them.
No I appreciate the question Raj and good morning, and so maybe I'll start and then I'll turn it over this three years ago, a little bit more in depth. The way that we think about our technology. It's really in two buckets. What we've tried to do is take validated gene therapy technology, that's been proven out in the clinic.
And essentially couple that with very targeted novel payload design. So so what does that mean to us validated gene therapy technology starts with a benign as the vector has been proven safe and effective across multiple indications in the clinical setting and now in the commercial setting with the approval of the old <unk> Jensen of up to about over 1000 patients that had been.
Treated to date.
The second piece of that is our use of <unk> delivery as the chosen the route of administration. This allows us to target the CNS broadly docs would be given interest equal medicine across multiple modalities.
And of safe and effective way in an outpatient setting.
It allows us to evade neutralizing antibodies by starting on the right side of the blood brain barrier and honestly the proof of it and the data when used in combination with the AAV nine in the clinic. You. This is the most notably demonstrated in the Abaxis Novartis, a strong trial, which reported data and that's the main last year the amicus feel in fixed trial.
When field and three trial, where they just actually update of their datasets recently at World Symposium and also the first enter typically deliver gene therapy trial, which was pioneered by our scientific.
Chief scientific collaborator Dr. Steven Gray and the collaboration with the NIH and giant axonal neuropathy, and so again, we feel strongly controlling for these key components of gene therapy improves overall probability of success from producers. This is extremely important where we've decided to what we've decided to innovate and be very targeted.
As it pertains to payload design. So in the case of US what does that look like you know where we are fortunate to have the first by the strike payload in the clinic, where we've essentially package to gene.
And of single a benign construct to deliver those two genes that the optimal one to one ratio. That's our program of GM too and in the case of Ret syndrome, we built in the self regulatory feedback loop the cap expression at wild type levels to guard against over expression of associated the toxicity, which is the real issue and ret syndrome, and we use our semi rare platform.
To do that in the case.
In some cases of the gene, it's just too big to fit inside of cell complimentary AAV nine so what we've done is we back the rise in RNA approach. This is our approach in Angelman, where we've taken a short hairpin RNA to target the silencing mechanism of the silent paternal allele in order to restore wild type of expression and to guard against over.
Suppression associated toxicity and in some cases, we want of knocked down the production of the toxic protein. This is the case of in our map T associated co op. At these programs. So again, we've been very thoughtful and targeted in the way that we've gone about payload design.
And really tried to pick the best payload for for that particular indication, but still wrapped in what we consider validated technology in the case of our GM to program. This is a bias the stronach.
Our bikes this round of construct single stranded with the PD two peptide linker and between the two the two genes in order to drive express running off of a single <unk>.
Promoter in order to drive expression at the optimal one to one ratio and we feel good about this construct because one we insure that we ensure the optimal endogenous one to one ratio by packaging both genes into a single construct but we're able to also take advantage of of cost correction because in the case of <unk>.
This particular lysosomal storage disorder like many of the enzyme here Hefei is the accretive. So the goal is to essentially transduce cells at an extremely high rate turn themselves into bio factories in order to the creep the enzyme out of that particular cell. So it can be taken up by sales that werent transduce by the construct so that's really the.
That's really the approach that's.
That's really the approach in GM too.
So, yes, I'll turn it over to you to see if you have any additional comments.
Thanks, Alright, thanks for the question.
I think you've covered the most of I think I'll just emphasize a couple of brief points. The first is there's always mentioned anything nine and interest income administration of HEK two non three mammalian cell.
<unk> product, we feel is the theory.
It's the best way of delivering drug to within the cell.
Specifically of very stable genetic medicine to within the south on the payload is one of the creativity and innovation comes in whether it's in price distorted by the sort of short ethanol or night.
The MRI ultra regulator element junior placement of therapy.
<unk>.
The approach to many genes and this is one of the more exciting things we've done recently, which is this.
This partnership with Dennis Law, the Cleveland Clinic in Anthonys focuses on the discovery of valuation.
I guess the translation of gene that's a foreign markets in particular into into clinical care of in the aggregate. These laws genetic clinical biological data sets really tightened the life of personalize the price to two two medicine now specifics of what he'll be doing it from the.
Looking at change the Dol are too big to fit in theory, the non cap set of wished.
There are a number.
Until the focusing specifically on our genetic epilepsies platform initially and what are you going to do is going to be what's the.
Matthaus These lost gene items and in the <unk>.
Very disciplined focused systematic way just.
The number of different constructs that.
Take house most of the non functional domains such that we can actually fit the.
The many gene therapy non cabinet Kelvin crammed those designs some of the Ucs W day trade the vector construct and stick several of them into the mouse model to demonstrate proof of concept for and select a specific concept for a particular disease and so that's one of the things we're more excited about.
Currently on the on the pilot of design elements.
Once again lot of focus will be on the genetic epilepsies currently.
Some of that.
Great. Thanks, and then just sort of a quick follow up on our.
Manufacturing can.
Can you just remind us the.
The the Abbvie on a program.
You have clinical material from from them I believe.
Is that.
The enough to go commercial or how is the process.
From clinical to commercial for that specific program their work. Thank you.
That's a great question Raj appreciate it so in our sealing one program, we actually received comparability material from from Abby O&M, which were actually transitioning to our commercially scalable heck 293 suspension.
Platform, which is what's going to actually be going into the clinic. So the goal with this particular study.
If the if the regulatory agency agrees it could be more of an adaptive design and basically what that means is that that study would be a phase 123 study all kind of within a single trial and the single protocol and the goal is to be ready to move quickly to commercialization of upon the end of that study and that basically means.
Treating patients with commercial grade GMP material.
So what we've done is we've actually initiated the GMP.
Are you factoring run through our partners at Cadillac and as you know Catlin as the only license.
CMO, that's actually actively producing.
A commercial AAV nine product indulgent, the mob and so we're pretty fortunate to have a strong strategic collaboration and the strong history.
With Cadillac, where they're actually producing this GMP material along with our Red syndrome material along with a couple of others. We're currently running for GMP runs concurrently across our manufacturing.
Cost of our manufacturing platform, which includes Cadillac, but also ut southwestern in order to meet our.
In order to meet our clinical needs. This year, so we're pretty fortunate to have.
Substantial capacity.
But we will be using commercial grade GMP material produced the Cadillac to treat the all in one we also have our chief Technical Officer, Brett border on the line Fred any additional comments.
No I think the alright, good morning, everyone. Our he is exactly right specifically regarding the seal on one program, we're partnering really closely with Cadillac and we're really deep into our tech transfer and manufacturing process for that program and like I already mentioned, we're partnering both with Cadillac for a number of our candidates that were pursuing.
Waiting for.
For the first the first in human studies this year as well as Ut southwestern.
And what we are leveraging from Abbvie on it as the plasmid construct the that was designed as part of that partnership.
Thanks, Brett.
And the additional questions Raj.
No I'm good thanks I appreciate it thanks.
Thank you. Our next question comes from Matthew Harrison with Morgan Stanley You May proceed with your question.
Great. Good morning, Thanks for taking the questions I guess two from me one just on.
On the G M to M C. I N D. In the U S is there any sort of the manufacturing or for comparability of the material that you need to do before you can file that maybe just remind us what you need to do in terms of filing that in the U S and <unk>.
You want to wait and include some clinical data.
Two of them to help the FDA on the dose and then second.
On an all in one on the I know you just talked about it briefly but I guess the the question here is.
Can you just think about how big that study actually needs to be I know that's of a pretty rare disorder.
And in terms of the.
How quickly I guess the real question is how quickly you might be able of malls such a study like that.
Thanks for the question, Matt Good morning, So maybe I'll take the second question first and allow us to use to go a little bit more in depth on boats. The all in one and G M too, but just to address the.
The epidemiology of the.
The all in one.
We expect that there is approximately.
About 900 to 1000 patients.
In the U S and Europe.
With the all in one infantile batten disease and there is the considerable founder's effect in certain parts of the world I E Finland.
And in Germany, where the prevalence of actually over expressed in and so we do know that there is a couple of clinical sites out there that have already identified a number of patients.
And that we don't think that there would be a substantial issue actually enrolling the study, albeit we do believe the study would be a global study.
And would have multiple sites around the world as in most of the most of the clinical trials that we're going after so we actually don't don't see that as an issue I'll pause there turn it over the two years, maybe three years do you have some additional comments on on what we're looking for in field in one and then maybe you want to comment on.
Our path to the U S study and GM too.
Sure.
With regards to CLR, one, yes as long as already mentioned, we have GAAP non in the U S. We have.
Sides of select since.
Currently.
And.
Both in the U S and also in Europe, We will also be.
Planning clinical trial activity of the sale of one program in Europe and.
Potentially broader.
Range mentioned sluggish the global study.
With the numbers of patients 900 to 1000 patients.
In the U S. Any of you currently.
Lots of a small study will only be necessary from a regulatory perspective, especially given the this huge unmet need is the disease, which results in early day.
Usually by the age of about six or seven.
And there is no current treatments available for this condition. So when you take all those things into consideration usually a small study will be enough to actually gain either full approval of the accelerates the treatment with some post marketing commitments.
I think the other thing I think it's important to remember for this particular program in terms of clinical trial operations of recruitment is actually.
The two large natural history studies that are ongoing one based in the U S and one based in Germany, and the speaking closely with the <unk>.
Investigators all of those on the <unk>.
Essentially the clinical trial sites, the patients will be able to rollover from the natural history study onto the drug study once the setup and we also have a nice background cohorts of.
Longer term prospectively collected natural history data, which as you know is.
It is very important from a rare disease perspective, and you might also be familiar with this recent guidance that was published by the FDA on.
The gene therapy development for neuro degenerative diseases, we spoke specifically about historical controls being critical of unimportant in the very valuable, especially if there is an unmet medical need, especially when the inclusion of of concurrent control may not be practical or ethical as will be the case in a disease where the.
Very rapid.
On the sites of rapid Cytol, let's say.
And.
Also when you build in the fact that we expect to see a loss of treatment effect, both from a biomarker perspective from the clinical perspective all of these.
<unk> is rolling to the fact that the.
There is ongoing natural history work both in the U S and in Europe during the beneficial for the enrollment in the operation loss of the Operationalization of the clinical trial. In addition to that we're also speaking with.
A key opinion leader in Finland, whether the filing of the mutation from this particular condition of the nice pool of patients the <unk>.
Anticipate enrollment of an issue.
And as we've already mentioned.
The we have of 99 day, the study should be kicking off in the second half of this year.
Let me start that will sail on one.
Any more questions on that.
Before I go on to GM too.
Yeah.
So yes that was great. Thanks.
Great.
On GM to I guess your question is.
And to make sure I'm answering the right question. This was.
The question of similarly, how are we going to operationalize the study.
The answer your question was really just about what you need to do to file the U S and if you want to wait for all of our certain amount of data to be able to provide the the FCA in terms of starting dose or other things that maybe could speed up the U S clinical study.
Sure.
I think the the only thing we're actually very comfortable with the starting dose as you know for these diseases.
Which are rare and severe we'd like to dose on the high side. So we're going in with a total dose of.
Five of <unk> 14, total of AG, which is of high dose being given the interests equally talks.
Targeting specifically the brain the CNS the pms tissue, the there's actually a low dose of enterprise systemically administered gene therapies, which are being given on the BG per kilo basis per se.
From a dose selection of prospective Russia quite comfortable what we are doing.
What we are doing in addition to.
The Canadian studies, we're doing some additional tox work and the rats specifically.
Specifically, a wild type of rat toxicology study.
Bill of tight discussions with the regulators and part of the reason we're doing this is just as you know at the moment of the FTA seem a little more conservative we have plenty of good tox data already.
Certainly towards the.
The on the equivalent in Canada.
But we just felt at the appropriate and as part of our general approach to mitigating risk from a tox perspective, we want us to additional Tox study and we have time to do that before it starts in the clinical trial in the U S. The GMC.
Which as you know will be in the second half of this year.
So.
And just the feeds into our general approach, the Tulsa culture, which I'll briefly mention which is we want to.
Really mitigate as much risk as possible early on so it's down to the price of a toxicology is three species. So NH pizza box routes Hawks plus.
Chronic mouse model talks.
Rich.
One of them back into the plans for all of programs unless the specific reason why we don't need all three.
I'll stop them assets at Us answer to your question.
Okay. Thank you Matt Operator next question.
Thank you and as a reminder to ask a question you will need to press star one on your telephone. Our next question comes from Byron Amin with Jefferies. You May proceed with your question.
Yeah, Hi, guys. Thanks for taking my question. So maybe just the start on G M. Two.
Can you just talk about how many patients you plan to enroll pace of enrolment in Canada, and then I think on the biomarker data later this year with.
With the Heck say, how much follow up of we get when you present, the standard and I guess what type of improvement.
Need to say.
Thanks for the question, so maybe I'll start and then I'll turn it over the studios for some specifics on what we're looking for and GM too. So the goal of the study in Canada is to enroll approximately four patient these patients would be.
Under 12 months of age so so essentially infantile infantile patients and we really believe the earlier your true youre going to have the better outcome and this would be consistent with multiple gene therapy clinical trials and clinical data that's been generated over the last few years of in the gene therapy space.
We're not doing is going to guide to kind of enrollment timing, but what we will do is guide to when we expect to have preliminary data, which we are.
We have publicly disclosed that we expect to have preliminary biomarker data in the second half of this year. So that's essentially what we're guiding to but essentially the enrollment target of that study of the approximately for patients and and and those patients would be under 12 months of the age.
Maybe you want to comment on kind of what we expect to see what we would consider I essentially I think the base of of the question of what we would consider a win in that clinical trial.
Sure absolutely I'll make one additional comment on the ROE and just just to let you know that.
Just the cadence of enrollment obviously with the spread disease gene therapy studies.
There's a little bit of a staggering between patient counts and role of them all at once even if you have from lined up just from a safety perspective, the types of patients observe the usually for a period of two to three months before this and the next patients and then because of that patient before dosing of the excellent. So there is that cadence to enrollments as well, but the needs to be taken into consideration.
From a why do it.
To see what we expect perspective.
I think once again with the most of our programs you've got to look at it from the perspective of the hesitancy from the bond market perspective, and then also what we're having to see clinically.
We anticipate seeing an increase in the heck of activity in the CSF per.
Hopefully of the one months after dosing time point, certainly I would expect to see the for the three months after dosing time points will the.
The bond market will be doing at the same time, we'll not just the.
The levels of enzyme.
But also looking at reduction of <unk> ganglioside, which is the accumulated substrate that the enzyme is.
Tempting to break down so we saw a nice true up in the gym to ganga side over time in our preclinical studies.
In the in the in the actual mass mass model. So we expect seeing the drop in the accumulation of substrate.
In the CSF.
In parallel to seeing the xa levels go up and.
As I've already mentioned I think the the.
<unk> of the level, we expect to see.
The bump up with one of the more we feel we would we should consider posted that kind of 5% of activity.
As with all of these secreted lifestyle of lines on a little bit of enzyme goes a long way because of the enzyme can breakdown wise from us and one so can lead the sell in to another so do the same thing and keep going from south of the cell to cell.
In line with the fact that the clinical phenotypes.
Closely correlate to biomarker levels, and you'll need a little bit to actually result in the normal lifespan, we think of little bit will go a long way instead of 5% levels of biomarkers should be more of them.
On the clinical side of things.
You'll never going to.
Recover lost neurons so with these diseases. These lost some storage disorders.
You've got the buildup of accumulative substrate in the license base well the rupture the leak out of their civic enzymatic contents on the cause damage to the neural tissue, which is what results in the ongoing progressive loss of neurons on the clinical free.
Features so you're never going to actually recover neuronal cells. Once one has gone it's gone which is why I already mentioned that the earlier we treat the.
The more lucky with the Hot zone.
A good outcome. So we're actually specifically dosing the younger patients and then Jim two studies. The two reasons first of all these the patients of the most severe disease and the highest unmet need but also if we can treat earlier before the rest of this.
<unk> for the neuro looks to take hold and that will be better.
Hope to see the full of at least the stabilization of.
The <unk>.
Most of the functions, so I would hope to see.
Stoppage and the loss of milestones and types of the stabilization of the the chop intend scores declining but also in addition to that given the recoverability and reverse the ability.
The recoverability in the plasticity associated with the brand and children I'd like to see some function of the cover from the months of perspective from a speech and language perspective, and also importantly, we'll.
Seizure activity for these kids.
One of the most distressing of this doesn't cost of disease type see some stabilization and some improvement on the reduction in seizure frequency at Tennessee of reduction of seizure medications and coupled with the improvements in quality of life and Catholic the burden.
Let me start with the and.
Hopefully that answered your question.
Great. Thank you.
Thanks Marion.
Thank you. Our next question comes from Kevin <unk> with Oppenheimer. You May proceed with your question.
Hi, Kevin Good morning.
Hi.
This is just the color on behalf of Kevin.
Just the.
Good morning can you hear me okay, yes.
Yes.
Hmm.
And then just the final question.
Can you tell us more of that the next generation technology platform from a party.
On the <unk>.
The other thing.
Where we are.
And what shall we expect for the next.
No great question and thank you for for asking it it's a platform we're actually quite excited about.
Initial data from our proof of concept study conducted by <unk>.
Our collaborators over at UT southwestern doctors, Stephen Gray and Rachel Bailey was actually presented at the <unk> last year, where they actually proved.
The fact that direct dosing to the vagus nerve could actually enable re dosing of AAV nine specifically and this was actually presented in an oral presentation last year at <unk>. So this was the technology, where we are quite excited about and quite excited to move forward into larger.
Animal studies later this year and hopefully eventually into the clinic.
I'll stop there and turn it over to see us and allow us to use to go through the actual process and what we would hope to see in the ongoing development of this platform.
Sure Yeah. Thanks perpetual question.
Yes, it's an interesting.
Our approach of really creative approach to trying to manage this issue of re dosing, which which as you know as is the.
A key a key issue for the sales.
Well I work side of that was actually for for all programs with brain tissue that doesn't turn over particularly.
Rapidly without we do expect to see durable sustainable effects without gene therapies, but having said that we do want to spend some time focusing on the stake on the re.
The dosing platform and there's two pieces to this.
Well, perhaps of what it involves is a direct injection of gene therapy. The same constant we're using to HEK two non three nine.
Nine.
Into the Vegas.
Access through the back of the neck. The vagus nerve is enough of it comes off the brain stem. So the 10th cranial the and it's actually quite accessible surgically athabasca than that now you can actually inject the small amounts of gene therapy drug and that and it travels often down both throughout the great on the retro grades transduction.
Along with the five us.
True up into the brain and full size throughout the whole of deal some moment the system. So it does two things. The first is it helps improve the features of.
The auto enrollment in the system dysfunction, which is often compromise the in many of the CNS and pain disorders. The we're managing but some of the Simpsons are often overlooked maybe.
Mainly because they relate more to the somatic.
Activity of the body of sequester conscious of tendency of the body.
Yes.
Things such as Guestroom some of them or utility.
Breathing the activity of the diaphragm the activity of the heart.
And the.
Blood pressure control.
For example in diseases, such as Red what you get you do get the ultimate in the system dysfunction, but you have these breathing of and the amount of business.
These periods of rapid.
Breathing followed by very slow shallow breathing with the quite distressing for the parents to see so there was no snow, making the system dysfunction that can be treated by the surprise from <unk> seen some very nice states was already mentioned in the preclinical models. The second of the past more important approach is the enables re dosing so once the AAV non <unk>.
It has been given interest equally.
She re administer when you administer directly into the banks and the and you can do that for two reasons.
Because of the interest the eco space is somewhat immune privilege just not fully even though privileged.
And also when you don't clean Jetblue the Vegas. The thus also somewhat imminent privileged because you're not getting antibodies crossing the blood brain barrier against the Interdealer space any downtime of the presence of antibodies and the bank of the tissue itself. So for those reasons. It was still well we may be able to read the excuse me the different approach simply by using the different routes of administration.
Ration of Steve's done some really nice work and has demonstrated.
In the animal model and the next steps to some more animal work and some of you should time points.
About <unk>.
Following the filing of the.
Start the clinical trials. So the of course from our guidance at the moment, we're still in the very early stages of preclinical work.
Just give me some background to what happened to achieve that.
Yes.
Thank you.
Thank you thanks for the question.
Thank you there are no further questions I will now turn the call over to Mr session for his closing remarks.
Thank you everyone for joining us on the call. We're very proud of what we accomplished in the year since our initial funding we have transitioned from a private to public and preclinical to clinical stage company. We have rapidly expanded our team with exceptional talent and advisors and we've advanced our next generation technologies and expanded our.
<unk> capabilities to support our unparalleled gene therapy pipeline, we look forward to the continued advancement of our programs and to keeping you updated on our progress. We hope you guys have a wonderful week. Thank you for joining us.
Thank you ladies and gentlemen.
Concludes today's presentation. Thank you once again for your participation you may now disconnect.
Yeah.
Yeah.
Okay.
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